(P27-040-23) δ-Tocotrienol Attenuates Inflammation-Induced Neuronal Insulin Resistance

Objectives: Insulin resistance is a hallmark of aging-related neurological pathologies. Neuroinflammation, commonly seen in aging, contributes to central insulin resistance. δ-Tocotrienol is a potent anti-inflammatory vitamer with neuroprotective effects. Tocotrienols modulate glucose homeostasis and improve insulin sensitivity in peripheral tissues. Increases in central insulin sensitivity may be a mechanism by which δ-tocotrienol provides neuroprotection. The objective of this study is to determine whether δ-tocotrienol mitigates the deleterious effects of inflammation on neuronal insulin signaling.

Methods: 80-90% confluent Neuro-2a cells were pretreated with vehicle or increasing concentrations of δ-tocotrienol for six hours followed by addition of a combination of lipopolysaccharide (LPS) and conditioned media from activated RAW 264.7 macrophages for 16 hours to induce inflammation. Two inflammatory transcription factors (STAT3 and NF-κB p65) and their signaling pathways were studied. To investigate insulin signaling, cells were treated with vehicle or insulin (100 nM) twenty minutes prior to protein collection in lysis buffer containing protease and phosphatase inhibitors.

Results: Insulin treatment induced Akt phosphorylation in Neuro-2a cells. LPS and macrophage conditioned media reduced insulin-stimulated Akt phosphorylation, and our preliminary data suggest that δ-tocotrienol may mitigate this reduction. Similarly, LPS and macrophage-conditioned media increased STAT3 phosphorylation at tyrosine⁷⁰⁵, and δ-tocotrienol reduced STAT3 phosphorylation. LPS and macrophage-conditioned media increased NF-κB p65 phosphorylation and expression of IκBα, but δ-tocotrienol (10 µM) had no effect.

Conclusions: The neuroprotective effects of δ-tocotrienol may be due to downregulation of STAT3 signaling, thus reducing inflammation-induced insulin resistance. The impact of δ-tocotrienol on inflammation and neuronal insulin signaling warrants further investigation. Tocotrienols may have potential in aging-associated neurological disorders.

Funding Sources: N/A